Abstract ABSTRACT The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Using IP Mass-spec analysis, we have identified a novel regulatory mechanism for the YAP oncogenic function via direct interaction with non-receptor tyrosine phosphatase 14 (PTPN14). PTPN14 interacts with YAP through PPxY domain, and overexpression of PTPN14 increases the inactive cytoplasmic form of YAP and decreases the transcriptional co-activator activity of YAP. Moreover, knockdown of PTPN14 induces nuclear retention of YAP and increases YAP-dependent cell migration. In summary, our study indicate a potential tumor-suppressor role for PTPN14 in the Hippo pathway and demonstrate a novel mechanism in YAP regulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-520. doi:1538-7445.AM2012-LB-520